The work proposed in this grant application is directed toward determining the mechanism of irreversible damage to ischemic myocardium and to ways of deducing or preventing this damage. The specific problems to be investigated relate to the effects of ischemia on energy production and the secondary alterations in cellular function and metabolism as a consequence of accumulation of products of anaerobic metabolism. Long-chain acyl CoA, long-chain acyl carnitine, lactate and hydrogen ion all accumulate to very high levels in the ischemic cell. These compounds are known to interfere with a number of enzymatic reactions and to have detrimental effects on the oxidative metabolism of mitochondria. The role of these compounds in decreased production of high energy phosphates during ischemia and the contribution to longer term onset of irreversible damage is a major portion of the proposed study.